Pharmaceutical actives are generally delivered using dosage forms designed to promote ease in using while encouraging maximum efficacy of the active. Among the challenges regarding creating dosage forms taken by mouth is formulating such a product in a form small enough to be easily swallowed.
When the desired dosage form is a liquid, then the pharmaceutical actives or actives must be solubilized in a vehicle wherein the composition is easy to use and maximizes therapeutic effectiveness. One such composition is a pharmaceutical suspension. A suspension is where solid active particles are dispersed within a liquid vehicle. Although suspensions are a very useful way to concentrate an active in a small volume, they possess some inherent disadvantages. One disadvantage is that over time the active particles settle to the bottom or float to the top of the liquid, resulting in a suspension that is not homogenous. Thus, a patient who uses a suspension in such a condition is likely to receive more or less active than the intended dose. In some cases this could result in a consumer taking a high and potentially a hazardous dose or conversely, a dose that lacks the minimum level of active required to provide the intended therapeutic benefit. Another disadvantage of suspensions relates to absorption of the active. For absorption to take place, a pharmaceutical active must first be in a solubilized state. Thus, suspensions that contain actives not previously solubilized must undergo dissolution in bodily fluids prior to absorption. Such a dissolution step may slow down the onset of the desired therapeutic effect.
In light of the disadvantages of suspensions mentioned above, those skilled in the art have created solutions in the form of elixirs and syrups for delivery of actives. These solutions can be easily and conveniently swallowed in 5, 10 or even 50 ml volumes. In certain cases, however, it is desirable to deliver the active in a true solution that is in a small volume of less than about 3 ml, even less than 1 ml. Up to now, achieving such small volumes has been problematic and for some actives nearly impossible. The problem is exacerbated where the dose level of the active is required to be large, or wherein the active agent is especially insoluble in the usual vehicles used for pharmaceuticals.
Liquid-filled, soft gelatin capsules were developed in response to this challenge. There are, however, limits to using such capsules. One limitation is when the requisite level of actives cannot be contained in a small volume. Liquid-centered, soft gelatin capsules containing acetaminophen has been the subject of a great deal of effort in order to solve problems such as those mentioned above. For example, in U.S. Pat. No. 5,505,961, assigned to R. P. Scherer reputes to have solved such problems associated with soft gelatin capsules, particularly where high dose levels of acetaminophen is required to provide therapeutic benefits. It is disclosed therein that acetaminophen, with or without other actives, is soluble in solvents including polyethylene glycol, water, propylene glycol, a solubilizing agent including potassium (or sodium) acetate and polyvinylpyrrolidone or PVP. It is disclosed therein, PVP is essential for inhibiting crystallization in such compositions. PCT Application WO 93/00072, Coapman, discloses a process for solubilizing pharmaceutical actives considered difficult to solubilize. This process requires PVP to aid in solubilizing the active agent and preventing precipitation. Similar limitation are disclosed for the acetaminophen solutions described in PCT Application WO 95/23595, by Dhabhar, wherein PVP is disclosed as an essential component of the compositions that are the subject matter of the patent.
PVP is a high molecular weight polymer that while inhibiting crystallization, also is responsible for increasing compositional viscosity of the liquid compositions. Such a viscosity increase is not significant for products contained in capsules intended for swallowing. The high viscosity associated with such liquid compositions containing PVP, however, does inhibit effective oral dosing of low volume products particularly from exact dosing implements such as medicine droppers, oral syringes, dosing cups and sachets. High viscosity liquid compositions are an impediment to being easily dosed from these types of exact dosing implements and do not spread easily over large surface areas of oral mucosal tissue.
When avoiding PVP and its related problems, new problems associated with oral dosing can develop. For example, U.S. Pat. No. 5,360,615, assigned to R. P. Scherer, discloses solubilizing the active by adding acid or base to cause the partial ionization of the active. It has been found, however, that this approach is undesirable in the case of liquid solutions to be delivered into the mouth for absorption through mucosal membranes since the active's ionization inhibits such absorption.
One very important consideration in choosing a product form, therefore, is determining the active's intended delivery site within the body. The prior art describing medicaments to be delivered to the stomach include liquid-center gelatin capsules. The liquids contained in these capsules are not intended to contact the body until the gelatin shell dissolves in the stomach. In such a product it is superfluous whether the liquid in the gelatin is highly viscous, or even a paste or solid. For administration into the mouth, however, the composition's ability to flow is critical. Low viscosity liquids permit accurate administration from current or developing exacting dispensing or dosing devices for administering a liquid composition to a person. Low viscosity liquids are easier to swallow and make the composition acceptably palatable. Such consumer acceptance is very important for encouraging consumers to comply with dosing instructions to receive the intended therapeutic benefit. Aside from the aesthetic considerations, it's desired that the formulation spread over a large surface area of mucosal tissue to enhance the diffusion of the respective actives within the formulation through the mucosal membranes.